The Relationship of IgE to Parasites and Atopy and Implications of Anti-IgE

 

Bob Lanier, MD

 

BACKGROUND

 

The global increase of atopia has spurred increasing interest into the relationship of a primal defense antibody system and the object of its displeasure.  As in most true scientific controversies, there are significant well-founded arguments to suggest both pro and con that eradication of parasites is not necessarily beneficial (1-9).  In the past, these conversations were merely academic and stimulating, but because of new technology, they have become very clinically relevant. It is particularly pertinent when using anti-IgE or parasitic molecules themselves as immunomodulary agents.  

 

GENETICS OF IgE AND PARASITOSIS

 

The interrelationships of parasitosis and immunity has been advanced through the work of Weiss and others  who characterized a specific human gene located on the 5th chromosome (5q31-33) which controls the level of IgE produced, especially in the presences of parasites. (7)  Additionally, the gene controlling IL-5 is involved in the susceptibility to shistasoma.  The high affinity receptor  FCeR1-e polymorphism on 11q13 is the Beta chain of the high affinity IgE receptor gene. (10,11)

 

THE IMPORTANCE OF IgE IN PARASITOSIS

 

The elaboration of IgE differs considerably according to the chronicity of infection.   Acute infections are seen mostly in children, migrants, and travelers and are associated with a mixed Th1/Th2 cytokine profile, marked eosinophilia and high but not extraordinary levels of IgE most of which is parasite-specific.  With respect to human helminthes, exposures may cause high eosinophila without actual infection.  Wheezing and urticaria are associated with ascariais, strongyloides and shistasoma, while angioedemia is common only with loa loa, and pulmonary eosinophilia is seen primarily with Wuchereria bancrofti. (13)  The primary defense with acute exposure is antibody dependant cellular cytotoxicity (ADCC) where the parasite is coated with specific IgE and attacked by eosinophils, macrophages and platelets.

 

Chronic infections are characterized by a shift of Th2, high levels of parasite specific IgG4, and extremely high levels of total IgE, of which only a fraction is parasite-specific.  These high levels of non-specific IgE may supersaturate the mast cells with impotent IgE promoting a decrease in allergic symptoms which might occur if there were free receptors available.  In addition to ADCC, IgA, IgG1, IgG2, and IgG4 are all shown to be involved as is IL-5 dependent IgM.   It is important to note that IgE plays little if any role in chronic trichura and ascariasis.(12)

 

While specific IgE may assist ADCC, IgE analysis of the literature suggests IgE itself has little specific role and is replaced by other antibodies if needed.

 

 

THE EPIDMIOLOGICAL ASSOCIATION BETWEEN PARASITOSIS AND ATOPY

 

The intriguing “Hygiene Theory” suggests that infectious exposure - or its lack - produces the climate for development of atopy.  On the one hand, because of a lack of bacterial infections (or viral infections through immunization), lower levels of IL-12 result in decreased Th1 stimulation which allows the “normal” bias of the immune system toward Th2 to be realized.  On the other hand, exposure to parasites may influence Th1 dominance.  In addition, skin test reactivity to aeroallergens is strongly associated with atopy in western countries – but not in Africa.(14-15 )

 

Masters et al (16), has shown a positive correlation between the lack of asthma and the presence of societal parasitosis.  However, Weiss suggests that the very rarity of asthma in those countries with endemic parasitosis renders these studies statistically weak and may make them powerless in proving a specific relationship.(16)  Indeed, a more powerful correlation may be socioeconomic and dietary issues.

 

CAN PARASITES CURE ASTHMA?

 

Interestingly, Turton (17) infected himself with hookworms and noticed a quick reduction in his asthmatic symptoms  In support of this inverse relationship, it is also clearly documented that treatment of a parasitic infection results in the emergence of positive skin tests and clinical allergic states.   Both phenomena may be explained by a “saturation concept”.  The very high levels of IgE generated by parasitic infection are in large part non-specific, and may saturate mast cells with impotent antibodies.  The decrease in symptoms may reflect the stoichiometric difficulty of specific antibodies to find room on their target cells.  Conversely, treatment of a parasitic infection with an accompanying drop in non-specific IgE may contribute to the competitive ability of specific antibodies to bind and produce symptoms.  Paradoxically, low intensity acute helminthes may cause the allergic symptoms described previously while high intensity and chronic infections may decrease allergic symptoms by “saturation”. (12)

 

 

THE RISK OF CRIPPLING IGE- THE IMPLICATIONS OF ANTI-IGE

 

The reduction of IgE, whether pharmaceutical or by anti-IgE monoclonal antibodies may actually improve the disease process of parasitosis in both human and animal models. It may lead to reduced worm burden and decreased egg production in shistasoma and P. westermani.  The mechanism of action is the suppression of non-specific IgE allowing more specific anti-parasitic IgE and IgE independent cellular toxicity enhanced by reduction of parasitic specific IgE to FCeR11/CD23 on macrophages and eosinophils

 

Theoretically, reduction of IgE by anti-IgE could produce more disease in travelers although the exposure in those people is likely to be short and transient.  Perhaps the larger concern is the inadvertent use of anti-IgE treatment in cases of existing parasitosis, particularly in cases of strongyloides because of the possibility of super infection.  But those individuals are likely to have an IgE of greater than 1000 and are therefore not good candidates for treatment with anti-IgE.  Screening for parasites is a lost art in many Western countries but it is being revisited as high IgE levels are being reported in patients under consideration for anti-IgE treatment. 

 

There is additional evidence of lack of danger from anti-IgE following an analysis of individuals in Brazil (unpublished Novartis study 2303).  137 patients (68 with anti-IgE and 69 on placebo) at high risk of infection with ascariasis were observed for one year. The geohelmith infection rate was slightly higher in the treated group (30) than the placebo group (24).   Clinically the course, severity, and response to treatment were the same.  There was no anaphylactic or hypersensitivity reaction to the study drug.

 

In western studies of anti-IgE (omalizumab) asthmatic and allergic patients, .19% of patients on active drug reported headlice, swimmers’ itch, pinworm, scabies, or amoebiasis compared with .16% of placebo treated patients. There was no difference in the intensity or duration of disease between the two groups.

 

 

USE OF PARASITIC MATERIALS AS IMMUNOMODULARY TREATMENT

 

Since parasitic infections consistently influence immune reactivity by mast cell hyperplasia, eosinophilia, and by increasing levels of non-specific and specific IgE, and since deliberate self-infection has resulted in clinical improvement, the use of parasitic molecules as an immunomodulary agent has been clinically intriguing.  The mechanisms of parasite invasion and resistance could be useful in the management of human auto-immune disease.

 

Mangan et al have demonstrated a novel immunomodulatory mechanism induced by S. mansoni worms dependent on an IL-10-producing B cell population that can protect against allergic hypersensitivity and block anaphylaxis in mice.(18)  Bashir has shown that enteric helminth infection protects mice against an allergic response to peanuts. (19)

Correlating evidence in humans is given by Medeiros as a low frequency of positive skin tests in asthmatic patients infected with Shistasoma mansoni who were exposed to high levels of mite allergens. (20).

 

Imai and Fujita have identified an IgE inducing factor, DiAG (Dirofilaria immitis –derived antigen), purified from filarial parasites suppressive in animal models of  allergy and insulin dependent diabetes mellitus (IDDM). (23)  The mechanism of action is twofold:  markedly reduced cellular immune reactions and polarization of T cell responses to Th2 and Th3 types and  stimulation of host immunoregulatory networks leading to the synthesis of anti-inflammatory cytokines (interleukin 10, transforming growth factor-beta (TGF-beta). Shea- Donahue et al have noted increases in interleukin-18, interleukin-9, chemokines, activation of nuclear factor kappa beta, and factors that alter host resistance in the development of host immunity, and for interleukin-13Ralpha2 receptor in down-regulating Th2 responses. (13)

 

The limitations of parasitic proteins include a risk of antigenicity although animal studies with DiAG have not produced specific antibodies and may have to be presented to the patient in a very low dose and sustained manner for immunomodulation. 

 

SUMMARY:

 

While IgE is traditionally considered important in parasite defense, there is little data to support a specific role except for epidemiological associations.  IgE may help control parasite numbers – but the immune system has redundancies which may be activated should IgE not be available.  Risk for travelers receiving anti-IgE treatment is low unless steroids or underlying immunodeficiencies are present.

 

REFERENCES

 

1. Hagel I, Di Prisco MC, Goldblatt J, Le Souef PN. The role of parasites in genetic susceptibility to allergy: IgE, helminthic infection and allergy, and the evolution of the human immune system.Clin Rev Allergy Immunol. 2004 Apr;26(2):75-83.

 

2. Yazdanbakhsh M, Matricardi PM.Parasites and the hygiene hypothesis: regulating

 the immune system? Clin Rev Allergy Immunol. 2004 Feb;26(1):15-24.

 

3. Levy DA Parasites and Allergy: From IgE to Th1/Th2 and Beyond. Clin Rev

 Allergy Immunol. 2004 Feb;26(1):1-4.

 

4. Holt PG.Parasites, atopy, and the hygiene hypothesis: resolution of a paradox? Lancet. 2000 Nov 18;356(9243):1699-701.

 

5. Hopkin JM.The rise of atopy and links to infection.Allergy. 2002;57 Suppl 72:5-9

Gale EA.A missing link in the hygiene hypothesis? Diabetologia. 2002 Apr;45(4):588-94. Epub 2002.

 

6. Finkelman FD, Urban JF Jr.The other side of the coin: the protective role of the TH2 cytokines. Allergy Clin Immunol. 2001 May;107(5):772-80.

 

7. Weiss ST.Parasites and asthma/allergy: what is the relationship? J Allergy Clin

 Immunol. 2000 Feb;105(2 Pt 1):205-10.

 

 

8. Lynch NR, Goldblatt J, Le Souef PN.Parasite infections and the risk of asthma and atopy. Thorax. 1999 Aug;54(8):659-60.

9. de Almeida MM, Arede C, Marta CS, Pinto PL, Daniel I, Peres I, Nogueira JA, Pinto JR. Atopy and enteroparasites.Allerg Immunol (Paris). 1998 Nov;30(9):291-4.

Masters S, Barrett-Connor E. Parasites and asthma--predictive or protective?
Epidemiol Rev. 1985;7:49-58.

 

10. Quinnell RJ. Genetics of susceptibility to human helminth infection.

 Int J Parasitol. 2003 Sep 30;33(11):1219-31.

 

11. Zinn-Justin A, Marquet S, Hillaire D, Dessein A, Abel L. Genome search for additional human loci controlling infection levels by Schistosoma mansoni.
Am J Trop Med Hyg. 2001 Dec;65(6):754-8.

 

12. Cooper, PJ Nutman, T, IgE and its Role in Parasitic Helmin Infections – Implictions for Anti-IgE based therapy, in  Ige and Anti-Ige Therapy in Asthma and Allergic Disease, 2002, Marcel Dekker 

 

13. Shea-Donohue T, Urban JF Jr Gastrointestinal parasite and host interactions. Curr Opin Gastroenterol. 2004 Jan;20(1):3-9.

 

14. Perzanowski MS, Ng'ang'a LW, Carter MC, Odhiambo J, Ngari P, Vaughan JW, Chapman MD, Kennedy MW, Platts-Mills TA. Atopy, asthma, and antibodies to Ascaris among rural and urban children in Kenya. J Pediatr. 2002 May;140(5):582-8.

 

15. van den Biggelaar AH, Lopuhaa C, van Ree R, van der Zee JS, Jans J, Hoek A, Migombet B, Borrmann S, Luckner D, Kremsner PG, Yazdanbakhsh M.

The prevalence of parasite infestation and house dust mite sensitization in Gabonese schoolchildren. Int Arch Allergy Immunol. 2001 Nov;126(3):231-8.

 

16.  Masters S, Barrett-Connor E. Parasites and asthma--predictive or protective?Epidemiol Rev. 1985;7:49-58.

 

17. Ogilvie BM, Bartlett A, Godfrey RC, Turton JA, Worms MJ, Yeates RA. Antibody responses in self-infections with Necator americanus.Trans R Soc Trop Med Hyg. 1978;72(1):66-71

 

18.  Mangan NE, Fallon RE, Smith P, van Rooijen N, McKenzie AN, Fallon PG. Helminth infection protects mice from anaphylaxis via IL-10-producing B cells. J Immunol. 2004 Nov 15;173(10):6346-56.

 

19. Bashir ME, Andersen P, Fuss IJ, Shi HN, Nagler-Anderson C.An enteric helminth infection protects against an allergic response to dietary antigen. J Immunol. 2002 Sep 15;169(6):3284-92.

 

20. Medeiros M Jr, Almeida MC, Figueiredo JP, Atta AM, Mendes CM, Araujo MI, Taketomi EA, Terra SA, Silva DA, Carvalho EM. Low frequency of positive skin tests in asthmatic patients infected with Shistasoma mansoni exposed to high levels of mite allergens.Pediatr Allergy Immunol. 2004 Apr;15(2):142-7

 

21. Imai S, Fujita K. Molecules of parasites as immunomodulatory drugs. Curr Top Med Chem. 2004;4(5):539-52.